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IMPORTANCEOveractivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.ObjectiveTo determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.DESIGN, SETTING, AND PARTICIPANTSIn an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).INTERVENTIONSPatients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days.MAIN OUTCOMES AND MEASURESThe primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.RESULTSOn February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).CONCLUSIONS AND RELEVANCEIn this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.TRIAL REGISTRATIONClinicalTrials.gov Identifier: NCT02735707

S U M M A R YSeismic observations suggest that a stably stratified layer, known as the F-layer, 150-300 km thick exists at the bottom of Earth's liquid outer core. These observations contrast with the density inferred from the Preliminary Reference Earth Model (PREM), which assumes an outer core that is well-mixed and adiabatic throughout. The liquid core is composed primarily of iron alloyed with a light component. A thermal boundary layer produces the opposite effect on the density profile compared with the observations, and single phase, thermochemical models do not provide a sufficient dynamic description of how light element is transported across the F-layer into the overlying liquid outer core. We therefore propose that the layer can be explained by a slurry on the liquidus, whereby solid particles of iron crystallize from the liquid alloy throughout the layer. The slurry model provides a dynamic explanation of how light element can be transported across a stable layer. We make two key assumptions, the first of which is fast-melting where the timescale of freezing is considered short compared to other processes. The second assumption is that we consider a binary alloy where the light element is purely composed of oxygen, which is expelled entirely into the liquid during freezing. We present a steady state 1-D box model of a slurry formulated in a reference frame moving at the speed of inner core growth. We ascertain temperature, light element concentration and solid flux profiles by varying the layer thickness, inner core heat flux and thermal conductivity, since there is some uncertainty in these estimates. Our solutions demonstrate that the steady state slurry can satisfy the geophysical constraints on the density jump across the layer and the core-mantle boundary heat flux.

The Rayleigh Ohnesorge Jetting Extensional Rheometer (ROJER) enables measurement of very short relaxation times of low viscosity complex fluids such as those encountered in ink-jet printing and spraying applications. This paper focuses on the design and operation of the ROJER. The performance of two nozzle designs are compared using Newtonian fluids alongside a study using computational fluid dynamics (CFD). Subsequently a disposable nozzle is developed that overcomes issues of blockage and cleaning.The operability of this design is subject to a focused study where low viscosity polymer solutions are characterised. The test fluid materials are ethyl hydroxy-ethyl cellulose (EHEC) and poly ethylene oxide (PEO) mixed with water/glycerol solutions. Results obtained by the disposable nozzle are encouraging, paving the way for a more cost-efficient and robust ROJER setup.